title: Different effects of the NMDA receptor antagonists ketamine, MK-801, and memantine on postsynaptic density transcripts and their topography: role of Homer signaling, and implications for novel antipsychotic and pro-cognitive targets in psychosis.
abstract: Administration of NMDA receptor antagonists, such as ketamine and MK-801, may induce psychotic-like behaviors in preclinical models of schizophrenia. Ketamine has also been observed to exacerbate psychotic symptoms in schizophrenia patients. However, memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease and proposed for antipsychotic augmentation, may challenge this view. To date, the molecular mechanisms by which these NMDA receptor antagonists cause different neurochemical, behavioral, and clinical effects are still a matter of debate. Here, we investigated by molecular imaging whether these agents could differently modulate gene expression and topographical distribution of glutamatergic postsynaptic density (PSD) proteins. We focused on Homer1a/Homer1b/PSD-95 signaling network, which may be implicated in glutamate-dependent synaptic plasticity, as well as in psychosis pathophysiology and treatment. Ketamine (25 and 50mg/kg) and MK-801 (0.8mg/kg) significantly induced the transcripts of immediate-early genes (Arc, c-fos, and Homer1a) in cortical regions compared to vehicle, whereas they reduced Homer1b and PSD-95 expression in cortical and striatal regions. Differently, memantine (5mg/kg) did not increase Homer1a signal compared to vehicle, whereas it induced c-fos in the somatosensory and in the medial agranular cortices. Moreover, memantine did not affect Homer1b and PSD-95 expression. When compared to ketamine and MK-801, memantine significantly increased the expression of c-fos, Homer1b and PSD-95. Overall, ketamine and MK-801 prominently increased Homer1a/Homer1b expression ratio, whereas memantine elicited the opposite effect. These data may support the view that ketamine, MK-801 and memantine exert divergent effects on PSD transcripts, which may contribute to their partially different behavioral and clinical effects.
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine "Federico II", Naples, Italy. Electronic address: adebarto@unina.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: de Bartolomeis
authors.forename: Chiara
authors.initials: C
authors.lastname: Sarappa
authors.forename: Elisabetta F
authors.initials: EF
authors.lastname: Buonaguro
authors.forename: Federica
authors.initials: F
authors.lastname: Marmo
authors.forename: Anna
authors.initials: A
authors.lastname: Eramo
authors.forename: Carmine
authors.initials: C
authors.lastname: Tomasetti
authors.forename: Felice
authors.initials: F
authors.lastname: Iasevoli
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology*; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D007649:Ketamine / Q000008:administration & dosage*; D008297:Male; D008559:Memantine / Q000008:administration & dosage*; D008565:Membrane Proteins / Q000096:biosynthesis*; D018697:Nootropic Agents / Q000008:administration & dosage*; D011618:Psychotic Disorders / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D002352:Carrier Proteins; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; C000606624:Homer1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018697:Nootropic Agents; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D016291:Dizocilpine Maleate; D008559:Memantine
keywords: ACC; ANOVA; Antipsychotics; Arc; BDNF; DEPC; Dopamine; EDTA; Glutamate; HSP70; Homer1; IC; MAC; MC; N-methyl-d-aspartate; NMDA; PBS; PSD; PSD-95; ROIs; S.E.M; SS; SSC; Schizophrenia; TdT; activity-related cytoplasmic protein; anterior cingulate cortex; brain-derived neurotrophic factor; core; core of the nucleus accumbens; diethylpyrocarbonate; dlCP; dmCP; dorsolateral caudate putamen; dorsomedial caudate putamen; ethylene-diamine-tetra-acetic acid; heat shock protein of 70kDa; insular cortex; mGluR5; medial agranular cortex; motor cortex; one-way analysis of variance; phosphate buffered saline; postsynaptic density; regions of interest; saline sodium citrate solution; shell; shell of the nucleus accumbens; somatosensory cortex; standard error mean; terminal deoxytransferase; type 5 metabotropic glutamate receptors; ventrolateral caudate putamen; ventromedial caudate putamen; vlCP; vmCP